Management of salivary gland tumors

Surgery after proper imaging (MRI or CT scan) is the main stay of treatment for salivary gland tumors. Although excision margins should be ≥5 mm for malignant tumors in cases of parotid gland carcinoma, the facial nerve should be preserved whenever it is not infiltrated. Adjuvant external radiation is indicated for malignant tumors with high-risk features such as close (or invaded) margins, perineural speed, lymphatic and/or vascular invasion, lymph-node involvement and high-grade histology. A Phase II trial testing adjuvant concomitant cisplatin plus radiation therapy versus adjuvant radiation therapy alone after surgery is currently under investigation for high-risk salivary gland cancer. For inoperable cancers, photons combined with proton boost seem to be a valuable option. Even if protons or carbon ions are promising, access to the latter is limited for usual treatment. For recurrent and/or metastatic cancer, polychemotherapy (cisplatin based) gives a 25% response rate in adenoid cystic carcinoma and should be used when the disease is overtly in progression. Targeted therapies with anti-EGF receptor molecules, antiangiogenic agents and tyrosine kinase inhibitors are ongoing, but more trials are needed to establish their efficacy, as is the use of bortezomib followed by doxorubicin. The products of fusion oncogenes, which have a pathogenic role in some adenoid cystic carcinoma and mucoepidermoid carcinomas, are of interest as potential therapeutic targets.     

Fast neutron radiotherapy for advanced malignant salivary gland tumors

Thirty-two patients with inoperable, recurrent, or gross residual malignant salivary gland tumors received fast neutron radiotherapy at the University of Washington. Eleven patients were treated with low energy neutrons alone, four received a combined photon-low energy neutron treatment regimen ("mixed beam"), and 17 were treated with high energy neutrons alone. Patients treated for microscopic residual tumor after a surgical resection were excluded from this study. With a minimum follow-up period of one year, (maximum 12 years), the overall locoregional tumor control rate for the entire series was 81%. The 5-year locoregional tumor control rate was 69%. The overall 5-year survival rate was 33% (50% for T3 tumors and 0% for T4 tumors). Compared to results obtained with conventional photon and/or electron treatment for advanced salivary gland tumors, fast neutron radiotherapy appears to offer a significant advantage.     

Radiation therapy in the treatment of malignant salivary gland tumors.

A retrospective analysis of 52 patients with malignant salivary gland tumors is reported. Seventeen patients received early postoperative radiation therapy and 16 (94%) were free of local or regional disease 2-14 years following initiation of therapy, although 14 were considered at high risk of developing local recurrence. Two subjects (12%) developed distant metastases and 14 (82%) were completely disease-free. Survival and disease-free status of patients treated for recurrent or inoperable disease were much worse with two of 13 disease-free at 45 and 168 months respectively. Various workers have reported recurrence rates after surgery along at 25-38% and over 50% for many histological types. On the basis of this report early postoperative radiation therapy is recommended to reduce the risk of postsurgical recurrence. Prognostic trends relating to both histological type and location of primary disease are discussed.     

Labial salivary gland tumors

A study was conducted on labial salivary gland tumors from four oral pathology laboratories. Of the 103 identified tumors, 87 (84.5%) were from the upper lip, whereas 16 (15.5%) were from the lower lip. Of the 87 upper lip tumors, 80 (92.0%) were benign. Forty-three of these were monomorphic adenomas and 37 were pleomorphic adenomas. Seven malignant tumors of the upper lip were as follows: four adenoid cystic carcinomas, two acinic cell carcinomas, and one adenocarcinoma. Of the 16 lower lip tumors, 15 (93.8%) were malignant. Thirteen of these were mucoepidermoid carcinomas and two were acinic cell carcinomas. The only benign lower lip tumor was an intraductal papilloma. These results confirm the findings of previous investigations, showing that minor salivary gland tumors are much more common in the upper lip than the lower lip, but that lower lip tumors are more likely to be malignant.     

Malignant salivary gland tumors

A retrospective review of 403 patients with salivary gland tumors seen between 1958 and 1980 and a mean follow-up of 10 years is reported. The median age was 58 (7-94) years and the male to female ratio 1.3:1. There were 293 (72%) parotid, 83 (21%) submaxillary and 27 (7%) tumors developed at other sites. Among these were 84 (22%) mucoepidermoid (all degrees of differentiation), 87 (22%) adenocystic carcinomas, 70 (17%) adenocarcinomas, 25 (6%) acinic, 26 (6%) squamous cell, 44 (11%) undifferentiated, 52 (13%) mixed and 12 (3%) nonspecified carcinomas. A painless lump was the first symptom in 338 (84%) patients. The first planned treatment was surgery in 110 (27%), radiotherapy in 50 (12%), and surgery and radiotherapy combined in 239 (59%) patients. Following the first treatment, the primary parotid tumor was controlled by surgery in 17/70 (24%), by irradiation in 6/39 (15%) and surgery and radiation combined in 134/182 (74%) patients. Altogether, regional metastases developed in 36 (12%) and distant metastases in 36 (12%) of 293 patients with parotid tumors. For the submandibular tumors the primary tumor was controlled by surgery in 9/31 (29%), 0/4 (0%) by irradiation, and in 32/46 (70%) by surgery and irradiation. Here, regional and distant metastases developed in 16/84 (19%) and 19/84 (23%) patients. Among the other sites the primary tumor was controlled by surgery in 4/9 (44%), 0/7 (0%) by irradiation, and in 8/11 (73%) by surgery and radiotherapy combined. In this group 4/27 (15%) and 5/27 (18%) patients developed regional and distant metastases. The 5- and 10-year cause specific survival rates were 65 and 59% for the parotid tumors, 61 and 48% for the submaxillary tumors and 62 and 52% for the other sites. These results clearly demonstrate the advantages of combining surgery and radiotherapy as the first planned treatment for most tumors.     

The role of radiotherapy in the treatment of malignant salivary gland tumors

PURPOSE: We analyzed the role of primary and postoperative low linear energy transfer radiotherapy in 538 patients treated for salivary gland cancer in centers of the Dutch Head and Neck Oncology Cooperative Group, in search for prognostic factors and dose response. METHODS AND MATERIALS: The tumor was located in the parotid gland in 59%, submandibular gland in 14%, oral cavity in 23%, and elsewhere in 5%. In 386 of 498 patients surgery was combined with radiotherapy, with a median dose of 62 Gy. Median delay between surgery and radiotherapy was 6 weeks. In the postoperative radiotherapy group, adverse prognostic factors prevailed. Elective radiotherapy to the neck was given in 40%, with a median dose of 50 Gy. Primary radiotherapy (n = 40) was given for unresectable disease or M(1), with a dose range of 28-74 Gy. RESULTS: Postoperative radiotherapy improved 10-year local control significantly compared with surgery alone in T(3-4) tumors (84% vs. 18%), in patients with close (95% vs. 55%) and incomplete resection (82% vs. 44%), in bone invasion (86% vs. 54%), and perineural invasion (88% vs. 60%). Local control was not correlated with interval between surgery and radiotherapy. No dose-response relationship was shown. Postoperative radiotherapy significantly improved regional control in the pN(+) neck (86% vs. 62% for surgery alone). A rating scale for different sites, T stage, and histologic type may be applied to calculate the risk of disease in the neck at presentation, and so indicate the need for elective neck treatment. A marginal dose-response was seen, in favor of a dose > or =46 Gy. A clear dose-response relationship was shown for patients treated with primary radiotherapy. Five-year local control was 50% with a dose of 66-70 Gy. CONCLUSIONS: Postoperative radiotherapy with a dose of at least 60 Gy is indicated for patients with T(3-4) tumors, incomplete or close resection, bone invasion, perineural invasion, and pN(+). In unresectable tumors, a dose of at least 66 Gy is advisable.     

Recurrent malignant salivary gland neoplasms

Recurrent salivary gland malignancies present difficult therapeutic decisions and poor prognosis in many instances, and treatment becomes of a palliative nature only. As many of the salivary gland malignancies we see are of the recurrent type, the following study was done to determine the efficacy of a vigorous attempt at retreatment. During the period January 1, 1960, through December 31, 1984, 352 patients with major and minor salivary gland tumors were evaluated at our institution. There were 149 benign lesions and 203 patients with malignant tumors. Of these, 99 patients had recurrent and metastatic tumors that had been treated initially elsewhere. Thirty-three of these patients were able to be treated with curative intent: surgery, 21; surgery plus radiation, 9; radiation therapy alone, 2; and radiation plus chemotherapy, 1. The 5 year survival with no evidence of disease was achieved in three patients with surgery alone and two patients with surgery plus radiation therapy. The group of five patients was comprised of two patients with adenoid cystic carcinomas of the parotid, one with intermediate grade mucoepidermoid carcinoma of the parotid, one, sebaceous cell carcinoma of the parotid, and one, adenoid cystic carcinoma of an accessory salivary gland. The results of this study serve to re-emphasize the relative poor yield of attempts at retreatment of loco-regional recurrence of salivary gland tumors.     

An update on malignant salivary gland tumors treated with neutrons at Fermilab

One hundred and thirteen cases of recurrent and/or unresectable malignant salivary gland tumors, treated with fast neutron therapy at Fermilab between September 1976 and December 1984, are analyzed for local control, sites of failure, and treatment-related morbidity. Sixty-three patients had major and 55 had minor salivary gland tumors. Local control was achieved in 67% of patients with major and 58% of patients with minor salivary gland tumors. In the subgroup of patients with oropharyngeal and oral cavity lesions, 19/24 (80%) had local control. However, only four of 15 patients with maxillary antrum tumors had successful control of their disease. Seventy-four percent of patients with lesions measuring 5 cm or less and 30% of patients with larger lesions had their local disease controlled. Histology did not influence the local control rate. Both observed and adjusted median survival for patients with major salivary gland tumors was 36 months. Disease-free survival was 31 months. Observed and adjusted median survivals for patients with minor salivary gland tumors are 48 and 57 months respectively. Twenty of 86 patients (23%) had major morbidity; this was directly related to the total dose delivered. In the dose range 20-24 Gy the complication rate was 16%. Most of these complications were successfully managed with minimal functional disability. We have concluded that fast neutron irradiation is an appropriate treatment for malignant salivary gland tumors.     

The role of immune surveillance in malignant transformation of benign salivary gland tumors

Pleomorphic adenoma (PA), the most common salivary gland tumor, is a benign tumor that carries a risk of malignant transformation to various histologies of carcinoma ex pleomorphic adenoma (CA exPA). Recently, genomic analyses have provided deeper insights into the molecular biology of salivary gland cancers. However, the molecular processes that underlie the progression from PA to CA exPA are largely unknown. In this study, we used RNAseq data from CA ex PA of myoepithelial (n = 24) or salivary duct histology (n = 6), de novo myoepithelial carcinoma (n = 16) and de novo salivary duct carcinoma (n = 10), and compared their constituent immune tumor microenvironments. We found that increasing levels of immune infiltration and activation were associated with a generally lower probability of cancer developing ex-PA, suggesting that immune surveillance may constrain the malignant transformation of benign salivary tumors. More immunologically infiltrated tumors were more likely to have developed de novo. Taken together, these data suggest a role for tumor escape from immune surveillance in the development of CA exPA. The immune-cold microenvironments of CA ex PA tumors may in part explain their more aggressive clinical behavior.     

Benign, malignant salivary gland tumors: comparison of immunohistochemical expression of e-cadherin

The aim of the present study was to assess any variation in the immunohistochemical expression of E-cadherin in benign and malignant salivary gland tumors. A total of 60 cases of benign and malignant salivary gland tumors were evaluated immunohistochemically for E-cadherin expression. These included 10 cases of pleomorphic adenoma (PA), 2 cases of canalicular adenoma (CA), 2 cases of myoepithelioma (MY), 24 cases of adenoid cystic carcinoma (ACC), 12 cases of mucoepidermoid carcinoma (MEC), 9 cases of adenocarcinoma (AC) and 1 case of carcinoma ex pleomorphic adenoma (Ca Ex PA). 48 cases (80%) showed positive expression, in which benign tumors exhibited relatively increased reactivity (85.7%) as compared to the malignant tumors (78.3%). 10 PA, 2 MY, 20 ACC, 9 MEC, 6 AC and 1 Ca Ex PA expressed E-cadherin. Negative expression was evident in CA, ACC, MEC and AC. Statistically significant reduction in reactivity was evident in mucoepidermoid carcinoma and adenocarcinoma, when compared to pleomorphic adenoma.     

Genomic landscape of salivary gland tumors

Effective treatment options for advanced salivary gland tumors are lacking. To better understand these tumors, we report their genomic landscape. We studied the molecular aberrations in 117 patients with salivary gland tumors that were, on physician request, tested in a Clinical Laboratory Improvement Amendments (CLIA) laboratory (Foundation Medicine, Cambridge, MA) using next-generation sequencing (182 or 236 genes), and analyzed by N-of-One, Inc. (Lexington, MA). There were 354 total aberrations, with 240 distinct aberrations identified in this patient population. Only 10 individuals (8.5%) had a molecular portfolio that was identical to any other patient (with four different portfolios amongst the ten patients).The most common abnormalities involved the TP53 gene (36/117 [30.8% of patients]), cyclin pathway (CCND1, CDK4/6 or CDKN2A/B) (31/117 [26.5%]) and PI3K pathway (PIK3CA, PIK3R1, PTEN or AKT1/3) (28/117 [23.9%]). In multivariate analysis, statistically significant co-existing aberrations were observed as follows: TP53 and ERBB2 (p = 0.01), cyclin pathway and MDM2 (p = 0.03), and PI3K pathway and HRAS (p = 0.0001). We were able to identify possible cognate targeted therapies in most of the patients (107/117 [91.5%]), including FDA-approved drugs in 80/117 [68.4%]. In conclusion, salivary gland tumors were characterized by multiple distinct aberrations that mostly differed from patient to patient. Significant associations between aberrations in TP53 and ERBB2, the cyclin pathway and MDM2, and HRAS and the PI3K pathway were identified. Most patients had actionable alterations. These results provide a framework for tailored combinations of matched therapies.     

The implications of improved treatment of malignant salivary gland tumors by fast neutron radiotherapy

The conventional treatment for cancer of the salivary glands is surgery, with or without X ray therapy. In advanced tumors (Stage III and IV), local control and 5-year survival rates are less than 35%. Radical surgery severs the facial nerve in the majority of operations on parotid gland tumors. Local control of unresectable salivary gland tumors was achieved, in 74% of cases, by fast neutron therapy. From the MRC cyclotron at Hammersmith Hospital neutrons were given to 65 patients, with locally advanced or recurrent tumors, 89% of which were Stage IV. Local control and 5-year survival rates were 72% and 50%, respectively. The facial nerve was not damaged by neutron therapy. In patients with parotid gland tumors, 77% regained or maintained function. Function was lost in 14% through recurrence and 9% remained paralyzed. The results were achieved using beams from primitive machines with serious disadvantages. The results from neutrons implicate improvements for locally advanced tumors of non-epidermal origin in other sites of the body, especially with the high energy neutrons now available from modern cyclotrons.     

Expression and mutation patterns of p53 in benign and malignant salivary gland tumors

The expression and mutation patterns of p53 were studied in a series of 68 benign pleomorphic adenomas and 237 malignant salivary gland tumors. p53 overexpression (nuclear staining exceeding 10%) was detected in 20% of the malignant salivary gland tumors, with the highest prevalence observed in polymorphous low grade adenocarcinoma, squamous cell carcinoma, and carcinoma ex pleomorphic adenoma and the lowest in adenoid cystic carcinoma and acinic cell carcinoma. In contrast, none of the 68 benign pleomorphic adenomas had nuclear staining exceeding 10%. SSCP and nucleotide sequence analysis of exons 4 to 9 of p53 in 19 malignant tumors revealed 9 mutations in 7 tumors. Our findings indicate that p53 may be a useful marker to help discriminate between benign and malignant salivary gland tumors.